Project Summary/Abstract: Understanding the complex circuitry within mammalian brains remains a major challenge, which, if met, will provide critical insight into brain function and could provide guidance for developing treatments of neurological disorders and diseases. In this regard, the ability to map and modulate the same neural network with cellular resolution over months to years would be vital for elucidating, for example, how existing neurons evolve into neural circuits with diverse dynamics through learning, or to understand aging-associated brain changes and cognitive decline caused by neurodegenerative diseases. This project will explore a new paradigm for seamlessly integrating electronics within the brain, termed syringe- injectable mesh electronics, to provide these key mapping and modulation capabilities. This approach centers on the development of networks of recording and stimulating electrodes with size, connectivity and mechanical properties similar to neurons and neural tissue, which are delivered by controlled syringe injection to form stable non-invasive implants within the central nervous system. Systematic longitudinal studies will be carried out to track neural activity with single-neuron resolution across multiple brain regions associated with impairment or dysfunction of motor control, memory and cognitive capability related to aging and Alzheimer's disease. Mesh electronic probes will be injected into the distinct brain regions of rodents that define relevant circuitry, and imaging studies carried out to characterize the neural network/mesh electronics structures. Long-term recording and analysis of neural activity will be used to illuminate circuit behavior associated with aging as well as Alzheimer's disease. Stimulator electrodes will also be integrated within the mesh electronics probes and will be used to modulate activity, which will provide further understanding of the complex system-level circuitry and point to potential therapeutic applications. In addition, the syringe-injectable mesh electronics will be developed for studies of other areas of the nervous system, including the retina and spinal cord, where it is difficult to implement more conventional rigid probes. Non-axial intravitreal injection will be used to deliver mesh electronics to the cup-like retina of mice in a minimally invasive manner. Chronic in-vivo studies of the mouse retina will be carried out to optimize mesh design for epiretinal unfolding, to define positions of the mesh electrodes with respect to fluorescently labeled retinal cells, and to record from different retinal cells when awake restrained mice are subjected to different visual stimuli. Last, syringe-injectable mesh electronics will be used in a new approach to integrate electrical probes for development of neural prosthetics for treatment of spinal cord injury. The mesh electronics will be injected between vertebrae in rodents and used to investigate interfacing of sensing and stimulation electrodes with the spinal cord in the presence and absence of spinal cord injury, with the ultimate goal of developing new therapeutic approaches for spinal cord injury.